Approximately 30 million individuals have died of AIDS and 33 million are currently infected with human immunodeficiency virus type 1 (HIV-1) worldwide. Highly active antiretroviral therapy (HAART) is currently the best treatment for HIV infection. HAART has dramatically reduced the rate of HIV-1 and AIDS-related morbidity and mortality. However, drug administration may result in drug therapy failure, which is associated with drug resistance mutations. Drug resistance significantly limits the clinical benefit of antiretroviral treatment. I am a D.D.S./Ph.D. dual degree student and this NIH F30 application proposes research that will thoroughly investigate the biological relevance of the A62V amino acid substitution in HIV-1 reverse transcriptase (RT). The A62V mutation is a substitution observed in HIV-1 clinical isolates that is associated with multi-drug resistance but is known not to be a resistance-conferring mutation. My preliminary studies have discovered that A62V increases HIV-1 mutant frequency. This is the first observation that this residue can influence HIV-1 mutagenesis. In this application, I propose 2 specific aims. In Specific Aim 1, I will investigate a) the role of A62V on virus fitness compared to wt virus using dual competition assay and b) the role of A62V on the efficiency of HIV-1 viral DNA synthesis by real-time PCR. I will also investigate the impact of A62V on HIV-1 mutagenesis in primary T-cells and macrophages using a single cycle replication assay. In Specific Aim 2, I will examine A62V in the context of known multi-dideoxynucleoside resistance (MDR) mutations. In particular, I will thoroughly examine these HIV-1 RT variants for effects on viral fitness, for effects on the efficiency of viral DNA synthesis, and effects on HIV-1 mutagenesis. A better understand HIV-1 population dynamics in the context of antiretroviral therapy is important for predicting disease progression, the durability of antiretroviral drug regimens, and for providing insights into potential vaccine approaches.